PROJECT SUMMARY Adverse childhood experiences (ACEs) - which includes physical/sexual abuse, neglect or parental mental illness - confer risk for psychiatric dysfunction not only to those directly exposed, but also to the next generation.1-3 However, mechanisms underlying these ACE-related intergenerational effects are unclear, significantly limiting a unique prevention opportunity. Our study aims to examine mechanisms by which maternal ACEs influence offspring neurodevelopment, with special focus on prenatal inflammation. Toward this end, we will enroll, in the Brazilian Universal Health Care system (SUS), pregnant women with (n=290) and without (n=290) a history of substantial ACEs and follow their offspring over the first two years of life focused on the neurodevelopment of cognitive control, a cornerstone in the future development of impulsive behaviors. First, we will start by testing associations between maternal ACEs and offspring brain-behavior development using infant MRI and behavioral assessments of cognitive control. Second, we will examine mechanisms underlying these associations, focusing on the role of prenatal inflammation and the placenta using techniques to examine DNA epigenetics and RNA sequencing, while also taking into account genetic influences. As suggested by preclinical research, we hypothesize differential effects of prenatal inflammation in male vs. female pregnancies. In addition, we will explore modifiable post-natal factors and their influence on offspring neurodevelopment, monitoring parental depressive/mood symptoms and conducting two in-home assessments of the family. Revealing mechanisms of intergenerational transmission of adversity, our study will set the stage for high-impact preventive research. We will establish research infrastructure within a So Paulo primary care clinic network in a high-risk, low-resource community where preventive effects can have their most substantial impact. This R01 proposal is designed to be highly responsive to the NIH-FAPESP Funding Initiative (NOT-TW-16-001), which aims to support collaborative international research between investigators in the US and a stellar research group in the State of So Paulo, Brazil.